WO2007099537A1 - Pro-nanodispersion for the delivery of cyclosporin - Google Patents
Pro-nanodispersion for the delivery of cyclosporin Download PDFInfo
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- WO2007099537A1 WO2007099537A1 PCT/IL2007/000264 IL2007000264W WO2007099537A1 WO 2007099537 A1 WO2007099537 A1 WO 2007099537A1 IL 2007000264 W IL2007000264 W IL 2007000264W WO 2007099537 A1 WO2007099537 A1 WO 2007099537A1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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Definitions
- the present invention is of a pro-nanodispersion preparation for the delivery of - cyclosporin, and in particular, of a pro-nanodispersion preparation which provides a delivery system with high bioavailability of cyclosporin and related substances, for example for ophthalmic administration.
- dispersion systems axe currently in use as, or being explored for use as, carriers of substances, particularly biologically active compounds. These systems are designed to protect the substance from the environment during delivery and to provide a controlled release of the substance to a targeted area.
- the goal is to target specific sites in the body using the dispersion.
- the goal is to prepare a drug carrier system that acts as a reservoir at the site of inj ection.
- Dispersion systems used for pharmaceutical and cosmetic formulations can be categorized as either suspensions or emulsions.
- Suspensions are defined as solid particles ranging in size from a few nanometers up to hundreds of microns, dispersed in an aqueous or nonaqueous medium using suspending agents. Solid particles include microspheres, microcapsules, and nanospheres.
- Emulsions can be defined as dispersions of one liquid in another, stabilized by an interfacial film of emulsifiers such as surfactants and lipids. Despite their long history, emulsions are used less often today than many other dosage forms due to the inherent instability. Emulsion formulations include water in oil and oil in water emulsions, multiple water/oil/water emulsions, microemulsions, microdroplets, and liposomes.
- a microemulsion is .a transparent or substantially transparent emulsion which is formed spontaneously or substantially spontaneously when its components are brought into contact.
- Microemulsions are thermodynamically stable and contain dispersed particles or droplets of a size less than about 200 run. Generally microemulsions feature droplets or particles having a mean diameter of less than about 150 mm. These particles may be spherical, although other structures are feasible, such as liquid crystals with lamellar, hexagonal or isotropic symmetries. Microerrmlsions are usually stable over periods in excess of 24 hours.
- Microemulsions can also be used as a "microemulsion preconcentrate", which -is a composition which spontaneously forms a microemulsion in an aqueous medium, for example in water, upon dilution, or in the gastric juices after oral application. Dilution of the microemulsion in water can be for example from about 1 : 1 fold to about.1: 10 fold ⁇ dilution.
- Emulsion based delivery systems are useful for certain applications, the delivering .vesicles are subject to physical rupture because of the delicate nature of the liquid/membrane/liquid structure. Emulsion based delivery systems also have relatively short release times. Further, it is difficult to isolate emulsion based vesicles from the aqueous media used for storage for subsequent reconstitution.
- microemulsions have been the only successful delivery systems for " certain types of pharmaceutical compounds; particularly compounds such as members of the cyclosporin class, which are cyclic oligopeptides.
- the cyclosporin class includes substances having pharmaceutical utility, for example as immunosuppressive agents, anti-parasitic agents and agents for the reversal of multi-drug resistance, as known and described in the art.
- cyclosporins include, but are not limited to, Cyclosporin A (also known as and referred to herein as "Ciclosporin”), Cyclosporin G, [0- (2-hydroxyethyl)- (D) Ser] 2- Ciclosporin and'[3'-deshydroxy-3'-ket- MeBmt] '- [VaI) 2-Ciclos ⁇ orin.
- Ciclosporin is the cyclosporin of formula (1):
- Ciclosporin is well known as an imnranosupressive agent. In addition, Ciclosporin is being examined for the treatment of autoimmune and inflammatory diseases. Since the original discovery of Ciclosporin, a wide variety of naturally occurring cyclosporins have been isolated and identified. Many further non-natural cyclosporins have been prepared by total-or semi-synthetic means or by the application of modified culture techniques. The class comprising the cyclosporins now includes, for example, the naturally occurring cyclosporins A through Z [c. f. Traber et al. HeIv. C'hir. Acta. 60: 1247-1255.1977; Traber et al.. HeI v.
- cyclosporins in which the -MeBmt- residue is present in isomeric form (e. g. in which the configuration across positions 6'and 7'of the-MeBmt- residue is cis rather than trans); and cyclosporins in which variant amino acids are incorporated at specific positions within the peptide sequence.
- Many of these members of the cyclosporin class exhibit pharmaceutical utility which may be comparable to that of Ciclosporin.
- Cyclosporins are characteristically highly hydrophobic and thus require a lipophilic carrier.
- the selection of a suitable carrier is particularly critical for the administration of cyclosporins, as the bioavailability of these compounds is known in the art to be highly variable, depending upon the properties of the carrier.
- these compounds are known to have bioavailability which may vary significantly between individuals. Such variation is particularly dangerous given the side effects of cyclosporins, such as nephrotoxicity.
- the suitable carrier must provide good bioavailability of cyclosporins which is substantially consistent between individuals.
- Cyclosporin Absorption and metabolism of Cyclosporin are highly variable from patient to patient. Following oral administration, the elimination of Cyclosporin is primarily biliary, with only 6% of the dose (parent drug and metabolites) excreted in urine. The disposition of the orally administered drug from blood is generally biphasic with a terminal half life in the range of 5-18 hours. The cyclosporine relationship between the administered dose and exposure is linear within the therapeutic dose range.
- Tmax ranges from 1.5 - 2.0 hours and administration of food is known to shows a slight decrease in AUC and Cmax.
- the drug is extensively metabolized by cytochrome P450-3 A present in the liver and to a lesser degree by the CYP-3A in the gut and kidney.
- the drug is also a substrate for the P-glycoprotein (PGP).
- PGP P-glycoprotein
- At least 25 metabolites have been identified in human bile, feces, blood and urine.
- the immunosuppressive activity is primarily due to the parent drug (Physician Desk Reference 59 th edition. Thomson NJ, 2005; 2346-2353).
- cyclosporins may be administered with a microemulsion carrier.
- the carrier generally contains a hydrophilic solvent, such as liquid PEG200-600 ethylene or propylene glycol, ethanol or propanol, Glycerin, water soluble fatty acid C6-C18 esters of sucrose, dimethylisosorbide, ethyl-acetate, glycofurol (fatty acid derivative of a cyclic polyol), PEG derivatives of tocopherol, or PEG-fatty acid esters; a surfactant such as Tween 20, various PEG (polyethylene glycol) derivatives or phospholipids; a water insoluble oil such as corn oil and other oils from plants and mixtures of oils; and Cremophor and similar PEG derivatives of castor oil or other fats which are used as an amphiphilic solvent, emulsifier, surfactant and so forth.
- a hydrophilic solvent such as liquid PEG200-600 ethylene or propylene glycol, ethanol or propan
- This formulation includes a hydrophilic phase, a lipophilic phase and a surfactant.
- the hydrophilic phase could be a C 1-5 alkyl di-or partial-ether of a mono-or poly-oxy-C2 2alkanediol, for example.
- PCT Application No. WO 96/13273 to Sandoz describes compositions for cyclosporin and other macrolide drugs such as Rapamycin, containing a hydrophilic phase which includes dimethylisosorbide and/or a lower alkyl alkanoic ester, a lipophilic phase and a surfactant.
- the particle size after dispersion can be 200 nm but is preferably 100 nm or less.
- the hydrophilic phase is PEG, propylene glycol and glycofurol or dimethylisosorbide (a bicyclic ether). The bioavailability of a composition containing cyclosporin and the carrier is not disclosed.
- PCT Application No. WO 97/19692 also to Sandoz, describes compositions which are based on PEG-derivatives of saturated hydroxy fatty acids such as PEG- hydroxystearate and a low alcohol such as ethanol or propylene glycol. Again, the bioavailability of such a composition is not disclosed.
- PCT Application No. WO 98/33512 to Novartis describes compositions for oral administration of cyclosporin which do not contain oil. Instead, these compositions contain a surfactant with HLB 10 or higher and a hydrophilic phase which is polyethylene glycol and/or a lower alcohol (not more than 12%). The formulations are preconcentrates which provide a particle size of 10 to 150 nm upon dispersion.
- compositions that are their ability to be stably contained within a hard capsule.
- bioavailability of cyclosporin is known to be highly variable, depending upon the carrier.
- PCT Application No. WO 97/04795 to POLI Industria describes compositions that must contain one polymer, linear or cross-linked PEG and poly (acrylic) or mixtures thereof and monoesters of fatty acids with a short alcohol. Again, the bioavailability of such a composition is not disclosed.
- U. S. Patent No. 5,583,105 to Biogel describes cyclosporin formulations composed of PEG esters of tocopherol and a lipophilic solvent, an amphiphilic solvent and ethanol. Again, the bioavailability of such a composition is not disclosed.
- U. S. Patent No. 5,614,491 to Dr. Rentschler GmbH describes formulations of PEG fatty acid monoesters as emulsifying agent and a polyol as solvent.
- U. S. Patent No. 5,798,333 to Sherman describes formulations composed of Tocophersolan and a polyhydric alcohol. Tocophersolan is a water soluble surfactant which dissolves cyclosporin only at a 7: 1 ratio.
- U. S. Patent No. 5,827,822 to Sangstat describes formulations of alcohol and a PEG surfactant forming particle size between 200 and 400 nm.
- European Patent Application No. EP 0760237 Al to Cipla describes a composition containing: vegetable oil triglycerides (castor, peanut, or coconut oil), phospholipid, a surfactant (T ween 20, polyoxyl-40-hydrogenated castor oil) and a hydrophilic solvent, propylene glycol.
- Japanese Patent Application No. 61 -249918 to Yutaka Mizushima describes a cyclosporine formulation featuring eyedrops.
- the eyedrops use oils such as soy bean oil, cottonseed oil, sesame oil, sunflower oil, corn oil, a squalene, an eicosapetaenoic acid and its ester, azone.
- the solvents disclosed are glycerol and water.
- Swiss Patent No. 641356 describes a cyclosporine formulation which features a transesterification product of a triglyceride with a polyalkylene glycol. These products can be transesterification products of two molar fractions of a triglyceride of a natural oil, such as corn oil, almond oil, peanut oil, olive oil and/or palm oil, which are again vegetable oil triglycerides.
- a natural oil such as corn oil, almond oil, peanut oil, olive oil and/or palm oil
- None of these disclosed background art carrier formulations features an organic solvent which is a lower alkyl ester of hydroxyalkanoic acid, such as ethyl lactate. Moreover, none of these disclosed background art carrier formulations features a combination of a surfactant with high HLB and a surfactant with low HLB. Furthermore, none of these background art carrier formulations is disclosed as having high bioavailability. Furthermore, none of these background art carrier formulations is disclosed as having a solid fat as a core component which results in a dispersion when mixed with aqueous media at room temperature.
- compositions for the administration of cyclosporins, particularly for oral administration which would provide a high bioavailability, and which would preferably contain an organic solvent which is a lower alkyl ester of hydroxyalkanoic acid and a surfactant which is preferably a combination of a surfactant with high HLB and a surfactant with low HLB and which may contain a solid fat.
- the present invention overcomes these deficiencies of the background art by providing a novel formulation for the administration of a cyclosporin.
- the novel formulation which is a pro- nanodispersion at room temperature, featuring solid particles of a relatively large particle size as described in greater detail below, can become a microdispersion at body temperature. Furthermore, the inventor has discovered that surprisingly the formulation, when stored in soft gelatin capsules at room temperature, is stable for more than 2 years, maintaining the same composition and particle size. Furthermore, the novel formulation provides excellent bioavailability characteristics as described in greater detail below.
- the formulation according to the present invention features an amphiphilic solvent which is characterized by being a lower alkyl ester of hydroxyalkanoic acid; a surfactant, preferably a combination of a surfactant with a high HLB
- the solid fat is a fat which is solid at room temperature but which preferably melts at a temperature of at least about 30 C and which more preferably melts at body temperature, such as a fatty acid ester.
- the solid fat comprises a triglyceride such as tricaprin.
- suitable solid fats include trilaurin, fatty acids and fatty alcohols of 10 carbons or more, esters of fatty acids such as ethyl stearate and hydrogenated triglycerides that are solid at room temperature and melt at a temperature of at least about 30 C, more preferably melting at body temperature.
- esters of fatty acids such as ethyl stearate and hydrogenated triglycerides that are solid at room temperature and melt at a temperature of at least about 30 C, more preferably melting at body temperature.
- there is a large difference between the HLB of the low HLB surfactant and that of the high HLB surfactant such that the low HLB surfactant preferably has an HLB of less than about 6, while the high HLB surfactant preferably has an HLB of greater than about 10.
- the low HLB surfactant has an HLB of less than about 4, while the high HLB surfactant has an HLB of greater than about 14.
- the high HLB surfactant preferably comprises Polysorbate 20 (for example Tween 20) and the low HLB surfactant preferably comprises Sorbitan oleate (for example Span 80). Polysorbate 20 has an HLB of 16.7, while Sorbitan oleate has an HLB of 4.3.
- the formulation also preferably features a phospholipid and an ethoxylated fat such as Cremophor or Poloxamers which are block copolymers of polyethylene glycol and polypropylene glycol.
- the preferred mean diameter of the particle of the resultant formulation is preferably greater than about 150 nm at room temperature (25 C) but is preferably less than about 100 nm, more preferably less than about 60 run, and most preferably from about 5 nm to about 50 nm from at least about 33 C, such that this particle size is achieved at body temperature.
- the term "pro-nanodispersion” includes those compositions featuring droplets or particles having a mean diameter of less than about 150 nm, and which spontaneously forms a nanodispersion or microdispersion in an aqueous medium, for example in water upon dilution, or in the gastric juices after oral intake.
- Dilution of the pro-nanodispersion in water can be for example from about 1 : 1 fold to about 1: 1000 fold dilution.
- nano-dispersion refers to a dispersion in an aqueous medium of particles or vesicles of 100 nanometers or less at body temperature.
- FIG. 1 shows the mean percent of drug (CsA) released versus time for test
- FIG. 2 shows the mean CsA concentration-time profiles after single oral administration of 200 mg of the drug given as soft gelatin capsules test ( ⁇ ) (Dexcel Ltd.) and known drug reference (Novartis Inc.) ( ⁇ ) to 24 healthy volunteers.
- the present invention is of a novel formulation for the administration of a cyclosporin.
- This formulation features an amphiphilic solvent which is characterized by being a lower alkyl ester of hydroxyalkanoic acid; and a surfactant, preferably a combination of a surfactant with a high HLB (hydrophilic/lipophilic balance) and a surfactant with a low HLB.
- the formulation further features a solid fat that is solid at room temperature but preferably melts at a temperature above 3O 0 C.
- the high HLB surfactant preferably comprises Polysorbate 20 (for example Tween 20) and the low HLB surfactant preferably comprises Sorbitan oleate (for example Span 80).
- the amphiphilic solvent is preferably ethyl lactate.
- Ethyl lactate is an amphiphilic solvent characterized by having an octanol/water coefficient of 0.06.
- the solid fat is preferably a fatty acid ester and is more preferably a triglyceride.
- the formulation optionally and preferably comprises a phospholipid.
- the formulation comprises an ethoxylated fat such as Cremophor or another similar substance.
- ethoxylated fat such as Cremophor or another similar substance.
- solid fat and liquid fat refer to fats which are solid or liquid, respectively, at room temperature.
- the composition of the present invention does not include an alkyl alcohol such as ethanol.
- the preferred particle size of the resultant formulation from at least about 30 C is less than about 100 nm, more preferably less than about 60 nm, and most preferably from about 5 nm to about 50 nm.
- the resultant formulation must have a particle size of less than about 100 nm at body temperature in order to be suitable for the administration of cyclosporin.
- the particle size at room temperature of the formulation of the present invention is at least about 150 nm, as the formulation forms a solid microdispersion, yet contrary to the teachings of the art, is still able to achieve a suitable particle size upon administration to a subject.
- the inventor has discovered that the particle size at room temperature does not control bioavailability, which is contrary to the teachings of the background art. It is possible to have formulations with the taught particle size at room temperature that exhibit poor bioavailability, while other formulations (such as the formulation of the present invention) may have particle sizes greater than that taught by the background art, yet may still have excellent bioavailability. Also in direct contradiction to the teachings of the background art, the pro-nanodispersion does not spontaneously form a microdispersion upon dilution in water of the desired particle size without the application of heat (namely the presence in the body of the subj ect to obtain particle size of less than 100 nanometers, as body temperature is about 37 0 C).
- the combination of these components has unexpectedly been shown to provide higher bioavailability than had been previously shown for formulations of cyclosporin.
- the formulations of the present invention have the advantage of not requiring stabilizers, such as anti-oxidants in order to obtain good stability characteristics.
- stabilizers such as anti-oxidants
- the excellent stability of the formulations of the present invention is due to the use of solvents such as ethyl lactate as described in greater detail below.
- Ethyl lactate and other members of this family of solvents, have unexpectedly good properties for such a formulation as the formulations of the present invention.
- ethyl lactate is miscible in both organic and aqueous solvents, since it is more hydrophobic than ethanol.
- Ethyl lactate has higher storage stability than ethanol.
- Ethanol is a highly volatile solvent, with correspondingly lower storage stability, such that the use of ethanol in the currently available background art formulations is a clear disadvantage of these formulations.
- cyclosporin any member of the cyclosporin class having pharmaceutical efficacy.
- the particularly preferred member of the cyclosporin class is Ciclosporin
- a suitable organic solvent must be selected.
- the solvent is preferably selected from the family of lower alkyl esters of hydroxyalkanoic acid.
- lower alkyl includes Cl to C4, for example ethyl.
- the preferred amphiphilic solvents of the present invention are Cl-4 alkyl-hydroxy alkanoic acid ester. More preferably, the amphiphilic solvent comprises ethyl lactate.
- Ethyl lactate (2-hydroxypropanoic acid ethyl ester), is a colorless liquid which is miscible with water, alcohol and ether. Ethyl lactate is considered to be suitable for human administration with an LD50 which was higher than 5 g/kg in mice when given an oral dose; however, surprisingly ethyl lactate was not previously taught as a suitable ingredient for pharmaceutical compositions.
- Ethyl lactate is amphiphilic and therefore possesses a number of characteristics. For example, the diffusion of ethyl lactate from an organic solution into water is much slower and controlled compared to highly hydrophilic solvents such as ethanol or propanol. This is an important feature as a fast diffusion may result in immediate precipitation when exposed to aqueous media and in the other hand, a solvent which diffuses too slowly may not form the desired particle size as the formed droplets are not spontaneously formed.
- one important parameter for the behavior of the formulation of the present invention is the rate of diffusion of the solvent from the hydrophobic mixture of the pro-nanodispersion, as the rate of diffusion determines the particle size and composition of the formed particles.
- a rapid rate of diffusion will result in precipitation of large particles from the aqueous medium, while a slow rate of diffusion from the pro-nanodispersion into the stomach liquid may result in improper particle formation and precipitation of large particles, or alternatively may cause the cyclosporin to be poorly integrated within the solid fat carrier of the present formulation. Also, it may cause one or more components in the stomach fluid to interfere in the process of particle formation.
- the rate of diffusion from the oil droplet into the aqueous medium is a very important feature, as it must be neither too rapid nor too slow.
- the diffusion rate is related to the partition coefficient.
- the partition coefficient of ethyl lactate is exactly on the border between hydrophobicity and hydrophilicity, with a value of 0.06, which means that 50% of the solvent is in the octanol hydrophobic phase and 50% is in the water phase. Therefore, the diffusion rate is neither slow nor rapid, but in fact is exactly in the middle.
- ethyl lactate combines the properties of an alcohol and an ester where the ester group provides hydrophobicity while the hydroxyl provides the hydrophilicity and the ability to form hydrogen bonding with water.
- a suitable surfactant is preferably selected, which is preferably a combination of a surfactant with a high HLB (hydrophilic/lipophilic balance) of at least about 10 and a surfactant with a low HLB of less than about 6.
- HLB hydrophilic/lipophilic balance
- a surfactant with high HLB is hydrophilic, while a surfactant with low HLB is hydrophobic.
- the combination of a surfactant with high HLB and a surfactant with low HLB is actually a combination of a hydrophilic surfactant and a hydrophobic surfactant.
- This combination has never been taught or suggested in the background art as being suitable for a pharmaceutical carrier for cyclosporins.
- the HLB of the surfactant has been specified in the background art, it has been given in the range of 8 to 20, which is clearly different from the combination of surfactants taught herein.
- the compositions of the present invention can be clearly differentiated from those taught in the background art on the basis of the preferred combination of a surfactant with a low HLB and a surfactant with a high HLB.
- Particularly preferred combinations of these surfactants feature a large difference between the HLB of the low HLB surfactant and that of the high HLB surfactant.
- the high HLB surfactant preferably comprises Polysorbate 20 (for example Tween 20) and the low HLB surfactant preferably comprises Sorbitan oleate (for example Span 80).
- Polysorbate 20 for example Tween 20
- Sorbitan oleate for example Span 80
- Span hydrophobic surfactants are a group of sorbitan fatty acid esters such as sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate and sorbitan monolaurate (Fiedler, H. P.,”Lexikon der Hilfsstoffe fur Pharmazie, Kosmetic und Angrenzende füre", Editio Cantor, D- 7960 Aulendorf, 3rd edition, 1989, pages 1139-1140).
- Span 80 is an example of a low HLB surfactant, with an HLB of 4. 3, and is sorbitan monooleate.
- Tween hydrophilic surfactants are a family of PEG sorbitan esters (polyoxyethylene-sorbitan-fatty acid esters), for example mono-and tri-lauryl, pahnityl, stearyl and oleyl esters of the type known and commercially available under the trade name Tween (Fiedler, H. P.,”Lexikon der Hilfsstoffe fur Pharmazie, Kosmetic und Angrenzende füre", Editio Cantor. D-7960 Aulendorf. 3rd edition, 1989, pages 1300- 1304).
- Tween 20 polyoxyethylene (20) sorbitan monolaurate
- Other types of Tween surfactants may also be useful for the compositions of the present invention.
- Tween surfactants are soluble in water but not in oil.
- the chemical structure of this family of surfactants features one, two or three short PEG chains, generally of about 5 to 20 ethylene glycol units, connected by an ester bond to sorbitan.
- These surfactants are produced by various companies (Croda, ICI, Sandoz, Mazer, Atlas) and may appear under various trade names, besides Tween: SorlateT"", MonitanTM, CrilletT” and so forth.
- Members of this family which are polysorbates 20, 21, 0, 60, 61, 65, 80 and 85 have an HLB between 11 and 16.7, and therefore would be suitable for the present invention as high HLB surfactants.
- Other suitable high HLB surfactants may be obtained from manufacturers such as
- sucrose fatty acid esters such as saccharose monopalmitate (HLB of 15) and saccharose monostearate (HLB of 11) or PEG-32 glyceryl laurate (HLB of 14).
- Suitable high HLB nonionic surfactants are polyethylene glycol (PEG) nalkanol esters of the Brij family such as Brij and 99 which have an HLB in the range of 12.4 to 16.9.
- Brij 56 is polyoxyethylene [10] cetyl ether and is an example of such a high HLB surfactant which can be substituted for Tween 20. Brij 56 has an HLB of 12.9.
- the formulation further comprises a phospholipid.
- a phospholipid is a phosphorylated diacylglyceride molecule or its derivative.
- the parent structure is diacylglycerol phosphate, or phosphatide acid.
- Phosphatidyl choline (lecithin) is the choline ester of phosphorylated diacylglyceride.
- Synthetic lecithins are available with acyl chain lengths ranging from 4 to 19 carbons.
- the preferred lecithins for biological applications are those with alkyl chain lengths in the biological range (10 to 18 carbons).
- Naturally occurring lecithin can be obtained from a variety of sources such as egg, bovine heart, or soy bean.
- Unsaturated lecithins (dioleoyl; dilinoleoyl; alpha-palmitoyl, beta oleoyl; alpha palmitoyl, beta linoleoyl; and alpha oleoyl, beta palmitoyl), dianachidonyl lecithin (highly unsaturated and a prostaglandin precursor), and alpha palmito beta myristoyl lecithin are also available.
- Certain phospholipids such as phosphatidic acid, phosphatidyl serine, phosphatidyl inositol, cardiolipin (diphosphatidyl glycerol), and phosphatidyl glycerol, can react with calcium in serum, causing aggregation or the binding of lipospheres to cell membranes.
- Phosphatidic acid can be isolated from egg or prepared synthetically (dimyristoyl, dipalmitoyl and distearoyl derivatives are available from Calbiochem).
- Bovine phosphatidyl serine is also available commercially (Sigma Chemical Co. St. Louis, Mo.).
- Phosphatidyl inositol can be isolated from plant or bovine sources.
- Cardiolipin can be purified from bovine or bacterial sources.
- Phosphatidyl glycerol can also be purified from bacterial fermentation.
- a solid fat preferably a fatty acid ester such as a triglyceride.
- a triglyceride is tricaprin.
- Tricaprin is a hydrophobic triester of glycerol and caproic acid. Tricaprin does not dissolve in water and thus remains as a component of the dispersed cyclosporm-loaded particles after dispersion in aqueous solution. Tricaprin solubilizes cyclosporin in a fatty medium which is dispersed by the hydrophilic-hydrophobic dispersing agents.
- fatty components which are suitable as replacement for tricaprin include, but are not limited to, pure and mixed alkyl esters of fatty acids and mixtures thereof. Examples include but are not limited to ethyl esters of fatty acids such as ethylstearate and ethylpalmitate triglycerides such as trilaurin and mixtures of solid fatty acid esters.
- Mixtures of fats include hydrogenated vegetable oils. The preferred fats are those that solubilize cyclosporin with a melting point between 25 and 37 C such that the resultant pro- nanodispersion formulation forms a microdispersion of solid particles which melt into a micro-dispersion at body temperature.
- the particle size of the pro-nanodispersion was measured with an N4-Coulter particle size analyzer, suitable for submicron particle size determination. Three drops of the pro-nanodispersion were added to five milliliters of water. The particle size of the pro-nanodispersjon did not change when the pro- nanodispersion was dispersed in five milliliters of HCl solution.
- the member of the cyclosporin class which was used for the experiments described below was Ciclosporin (Cyclosporin A).
- the formulation features Ciclosporin as the active ingredient (this Example includes lOOmg of the active ingredient, but as described herein, other dosages may optionally also be provided).
- the solvent comprises ethyl lactate.
- the formulation features a solid fat, which in this Example is triglyceride (such as Tricaprin for example).
- the formulation also features a combination of a low HLB solvent and a high HLB solvent as described herein; for this Example, the combination comprises Polysorbate 20 and Sorbitan oleate.
- the formulation features a phospholipid (in this Example, preferably lecithin).
- the formulation features an ethoxylated fat such as Cremophor for example. Table 1
- particle size upon mixing 1 ml of the pro-nanodispersion with 10 ml of water at body temperature was found to be 30 nm. No effect was found upon varying the pH of the water from about 2 to about 10.
- Example 2 Effect of Solvent on Particle Size
- An exemplary composition containing Ciclosporin, solvent, TRC (tricaprin), egg phospholipid (Avanti, USA), Tween 20, Span 80 and Cremophor was prepared with increasing amounts of ethyl lactate, as given in Table 1 (all amounts of ingredients are given in milligrams). The effect of adding increasing amounts of these ingredients to the composition of the present invention on (mean) particle size is also given in Table 2. Briefly, all compositions which contained ethyl lactate had a particle size of less than 100 nm at a temperature of 37 0 C. The particle size decreased as the amount of ethyl lactate was increased. Table 2: Effect of Solvent on Particle Size
- compositions provided a liquid solution. When dispersed in deionized water at 37 0 C , all compositions which contained Span 80 had a particle size of less than 100 nm. The particle size decreased as the amount of Span 80 was increased. Table 3: Effect of Surfactant on Particle Size
- compositions containing Cyclosporin were prepared as described in Table 4 (all amounts of ingredients are given in milligrams). The effect of these ingredients on the particle size of the pro-nanodispersion solution when dispersed in warm water at 37 0 C is also given in Table 4. Briefly, compositions which had both low and high HLB surfactants (such as Tween and Span) had a particle size of less than 100 nm at this temperature (which is body temperature). Tween and Cremophor can be substituted for each other as high HLB solvents (HLB > 10) but a certain amount of either surfactant is required to obtain a suitable particle size, depending upon the quantities of the other components.
- HLB high HLB solvents
- a combination of Tween 20 and Cremophor permits the use of reduced amounts of each ingredient, as described in greater detail below.
- a solvent such as ethyl lactate
- a solid fat such as tricaprin is also optional.
- the presence of a phospholipid is also preferred to obtain a particle size in the range of 30 nm, although the particle size remained below 100 nm even without the phospholipid as for Formulation 3, in which no phospholipid was added but the particle size was 95 nm at 37 0 C.
- Table 4 Effect of Other Ingredients on Particle Size
- Example 1 The composition of Example 1 was prepared at two different total quantities (all amounts of ingredients are given in milligrams), with the second quantity featuring 10- fold larger amounts of each ingredient. Both compositions were easily prepared by dissolving all components to a liquid solution by mixing with mild heating (about 40 0 C). Preferably, the phospholipid was first dissolved in ethyl lactate, and then all other components were added with continuous mixing, apart from Cyclosporin which was added- last. The mean particle size of the composition was measured after dispersion of different amounts of the composition in deionized water at 37 0 C by using the light scattering technique with a Coulter N4 particle size analyzer. Both volumes of the composition had a particle size in the range of 30 nm which is preferred This composition was used for human studies, as described in greater detail below.
- the stability of the composition was tested by loading doses of 50 mg of Ciclosporin into hard gelatin capsules (size 00) or in glass containers and then storing the composition at room temperature (25 0 C) or at refrigeration (4 0 C).
- the particle size and the Ciclosporin content were determined after 3 and 6 months of storage.
- AU samples were found to have a particle size in the range between 17.2 and 32.6 at any dispersion range (3 to 20 drops per 5 ml) when measured at a temperature of 37 0 C.
- the Cyclosporin content for all stored formulations was between the required limits of 95 to 105% of the initial concentration even after 2 years of room temperature storage.
- the formulation of this invention preferably uses tricaprin (a solid fat that has a melting point of 32 0 C) as the hydrophobic core component of the particles, while Neoral® formulations use corn oil (liquid at room temperature) as the core component of the particles.
- Example 1 The formulation of Example 1 was prepared with the addition of 2mg of Nile Red as hydrophobic fluorescent marker.
- the nanoemulsion formulation was prepared with the addition of 2 mg Nile red using the Neoral® (commercially available) formulation ingredients for the preparation of 1200 mg of formulation.
- the formulations were placed on a suitable slide and examined under the Confocal microscopy at room temperature. Confocal microscopy (lens #20) picture showed particles of various sizes in the range of 0.2 to 1 microns for the formulation of the present invention.
- the Neoral® formulation did not show any particles but a continuous view which indicates the presence of a nanoemulsion.
- Sample preparation 0.5 ml of both formulations at a temperature in which they are in a liquid or "oily” form was added to 2 ml of double distilled water (25 0 C) and hand shaken for a few seconds until mixing was uniform.
- the Neoral® formulation formed a clear solution while the formulation of the present invention formed a milky like dispersion.
- the formulations in oily form were dispersed in warm water (37 0 C) and the dispersion was viewed by microscope. Both formulations formed almost clear solutions that do not show any particles under confocal microcopy due to its low sensitivity.
- the particle size of the dispersed formulation at 25 0 C and at 37 0 C was determined using Coulter N4 particle size analyzer.
- 0.2 ml of cyclosporin oil formulations taken from soft gelatin capsules of Neoral® or the invented formulation were added to 5 ml double distilled water at 25 0 C or at 37 0 C and hand shaken for a few seconds to form a uniform dispersion.
- the dispersions were analyzed for their particle size.
- the formulation of the present invention showed a mean particle size of 0.5 microns with most particles in the range of 0.2 to 0.8 microns when dispersed in water at 25 0 C while the Neoral® formulation showed a particle size of 30.2 nanometers.
- the formulations at 37 0 C showed a particle size of 33.6 nanometers for the formulation of the present and 32.6 nanometers for the Neoral® formulation.
- the precipitate from the invented formulation was dried in room air over night and the pellet was analyzed by Differential Scanning Calorimeter (DSC Metier) for melting point.
- the melting point of the precipitate was 30.4 0 C which indicates that the dispersion is a suspension of solid particles at temperatures below the melting point.
- the cyclosporin formulation of the present invention forms a microdispersion, when dispersed in water at ambient temperature (25 0 C).
- the formed solid particles have a particle size greater than 0.2 microns, and included particles in a range of up to about 0.5 microns, with a melting point of 3O 0 C.
- the Neoral® formulation formed a true nano-emulsion of oil droplet size of 30 run at ambient temperature.
- the comparative drug release rate was assessed using a dissolution apparatus test according to the USP-24 method. Both formulations achieved an in-vitro release rate of more than 90% within 15 minutes. Methods and results are described in greater detail below.
- the dissolution apparatus was a 2 paddle apparatus, containing 0.1 N HCL, containing 4 mg of lauryldimethylamine-N-oxide per ml as the dissolution medium.
- the capsules were dissolved in a volume of 1 liter of the dissolution medium, at a temperature of 37 0 C and a rotation speed of 75rpm.
- samples were withdrawn from the dissolution apparatus and were assayed with an HPLC apparatus to determine the level of cyclosporin in the sample.
- the mobile phase featured a mixture of 0.05 M phosphoric acid and tetrahydrofuran, at a ratio of 59:41 volume per volume.
- Table 6 shows the amount of ciclosporin released from each formulation at the various timepoints.
- Figure 1 shows the mean percent of drug (CsA) released versus time for test (Deximune ® ) ( ⁇ ) and reference Neoral ® 100 mg ( ⁇ ) using USP 24 method. Both test and reference products exhibited very similar dissolution profiles. Both formulations showed a very fast release rate with more than 90% of the drug released and dissolved within 15 minutes (Fig. 1). The release rates for both formulations were superimposable.
- Example 7 shows the mean percent of drug (CsA) released versus time for test (Deximune ® ) ( ⁇ ) and reference Neoral ® 100 mg ( ⁇ ) using USP 24 method. Both test and reference products exhibited very similar dissolution profiles. Both formulations showed a very fast release rate with more than 90% of the drug released and dissolved within 15 minutes (Fig. 1). The release rates for both formulations were superimposable.
- Example 7 shows the mean percent of drug (CsA) released versus time for test (Deximune ® ) ( ⁇ ) and reference Neoral ® 100 mg ( ⁇ ) using US
- Example 5 The composition of Example 5 was prepared 5 times independently for 400 mg Ciclosporin. The particle size, Ciclosporin content, the morphology of the formed particles and the melting point of the particles was determined. The bioactivity of the Ciclosporin formulation on T-cells was also determined.
- the particle size of all formulations ranged between 18 to 29 nm when dispersed at 37 0 C in deionized water or 0.1 N HCl solution.
- the particles were viewed by Transmission Electron Microscope (TEM) at high magnification. Spherical particles with a narrow size distribution in the range of 30 nm were observed.
- the melting point of the particles was determined by differential scanning calorimeter (DSC) and was found to be in a temperature range of from 30 to 35 C.
- the composition was highly effective at inhibiting the activity of T-cells. The results clearly indicate the superior stability, reproducibility and efficacy of the preferred formulation.
- Example 1 The investigation was designed as a randomized, open-labeled, two-period, two- treatment crossover study, in 24 healthy fasted male volunteers. The subjects were administered a single 200mg cyclosporine (CsA) dose of either formulation.
- CsA cyclosporine
- the study protocol was a randomized, two-treatment, two-period, crossover investigation with a washout phase of one week between the two study periods.
- the treatments consisted of a single oral 200 mg dose (2 x 100 mg soft gelatin capsules) with 240 ml water.
- Subjects were confined to the study center from 10-12 hours before until 24 hours after each drug administration. On the days of drug administration, they fasted for 12 hours before dosing until 4 hours after dosing. Thereafter they were given standard, scheduled meals that were identical on both dosing days. The time of day of drug intake was identical for a given subject for each dosing. Fluid intake was also standard, and no alcohol or xanthines were allowed during the periods of confinements.
- the two one-sided hypotheses at the 5% level of significance were tested for AUC and Cmax, by constructing the 90% confidence intervals for the ratio between the test and reference averages.
- the range for concluding bioequivalence was set to 80%-125% using the logarithmically transformed data and the Tmax was evaluated by using the nonparametric analysis for the median difference were computed, all based on the EU and FDA guidelines .
- Figure 2 shows the mean CsA concentration-time profiles after single oral administration of 200 mg of the drug given as soft gelatin capsules test (D) (Dexcel Ltd.) reference (Novartis Inc.) ( ⁇ ) to 24 healthy volunteers.
- a further difficulty is the very poor solubility of cyclosporin A in water, which frequently leads to precipitation of cyclosporin A from aqueous-based eye-drops, causing major irritation of the eye.
- Restasis® produced by Allergan
- a topical, ophthalmic formulation which causes less irritation to the eyes, is better adapted to evenly distribute cyclosporin A in the eyes and does not cause precipitation of cyclosporin.
- a stable formulation of cyclosporine that remains in an anhydrous form in storage, while still being capable of dispersion into a microparticulate formulation shortly prior to administration is preferred.
- Such a formulation can be mixed with water to form a microdispersion which is stable for a few weeks of treatment.
- the formulations of the present invention can be mixed with a sterile aqueous medium that is suitable for eye drops to form a dispersion featuring 0.01 to 10 mg/ml of cyclosporin as active agent (after dilution).
- a sterile aqueous medium that is suitable for eye drops to form a dispersion featuring 0.01 to 10 mg/ml of cyclosporin as active agent (after dilution).
- These clear diluted dispersions can optionally be administered in the eye with a conventional eye dropper.
- the formulation is optionally and preferably stored as a pro- nanodispersion in the bottle while at the time of initial treatment, the pro-nanodispersion formulation is diluted with isotonic sterile buffered solution to form a concentration of from about 1 mg/ml to about 0.01 mg/ml.
- These dispersions require little or no preservative as the formulation is preferably mixed with water shortly before use.
- the pro-nanodispersion is optionally pre-mixed with the buffer solution and packed in single use vesicles or in a multidose bottle which may optionally contain benzyl alcohol or chloramphenicol as preservative for example.
- Non-limiting examples of other illustrative preservatives with suitable, exemplary amounts include benzalkonium chloride, 0.004 - 0.01 %; edetate sodium 0.02 - 0.05%; Phenylmercuric acetate or Phenylmercuric nitrate 0.002%; and/or Chlorobutanol and Benzyl alcohol 0.5% (the pH of the solution is preferably buffered to 5.0-5.5)
- a preferred formulation features cyclosporin in a pro-nanodispersion system comprising polysorbate- 20 and polyoxyl 40 hydrogenated castor oil that are approved for ophthalmic solutions.
- Sorbitan monooleate is considered as safe for eye formulations ("Handbook of Pharmaceutical Excipients", 4 th edition , 2003), while lecithin and solid triglyceride are considered as safe for use in ophthalmic formulations.
- the solvent ethyl lactate is considered to be safe, as ethyl lactate is a food additive although it has not been used yet in eye formulations.
- the ophthalmic compositions are preferably formulated as pro-nanodispersions, which upon mixing with saline suitable for eye drop formulations, form a microdispersion.
- pro-nanodispersions upon mixing with saline suitable for eye drop formulations, form a microdispersion.
- Cyclosporin is preferred as the active ingredient (this Example includes 10.00 mg of the active ingredient, but as described herein, other dosages may optionally also be provided).
- the solvent preferably comprises ethyl lactate, but may optionally comprise N-C 1-4 alkyl pyrrolidone, optionally and preferably N- methyl pyrrolidone, used in a similar amount as for ethyl lactate.
- the formulation may optionally and preferably comprise a solid fat, which in this Example is a solid triglyceride (such as tricaprin or trilaurin for example).
- the formulation also preferably features a combination of a low HLB solvent and a high HLB solvent as described herein; for this Example, the combination comprises Polysorbate 20 and Sorbitan oleate.
- the formulation features a phospholipid (in this Example, preferably lecithin). Also preferably, the formulation features an ethoxylated fat such as Cremophor for example.
- a phospholipid in this Example, preferably lecithin.
- the formulation features an ethoxylated fat such as Cremophor for example.
- the different examples of ingredients previously described in the specification may also optionally be used for the ophthalmic formulation, as long as the ingredients are specially formulated for use in the eye (and/or are otherwise approved for use in the eye). Exemplary ranges of amounts of different materials are given in Table 8 below as milligrams of material per 10ml of formulation (the amount in parentheses is for mg per ml formulation).
- the amount of each component is preferably determined according to the amounts of the other components. For example, reducing the amount of hydrophilic surfactant (Polysorbate 20) may require increasing the amount of Cremophor.
- Table 9 shows an exemplary optical formulation according to the present invention.
- particle size upon mixing 100 mg of the pro-nanodispersion with 10 ml of water at body temperature was found to be less than 200 nm.
- This pro-nanodispersion formulation is stable for more than one year when kept at room temperature in a sealed glass vial. Prior to use, the bottle is opened and 10 ml saline for eye drops is added and shaken gently to form immediately a translucent dispersion which does not cause irritation to the eye.
- a diluted formulation of 0.1 mg/ml of the formulation described in Table 9 was instilled in the eye of a rabbit every 30 minutes over a period of 4 hours. The eye was inspected for any adverse effects. No adverse effects were noted immediately or one week following the treatment.
- osmolarity maintainer which is more preferably glycerin, is included.
- Table 11 shows an exemplary, illustrative preferred formulation. Percentage of each ingredient is shown before and after dilution 170 times. Table 11
- Exemplary formulations were tested on rabbits. For each rabbit, one eye was tested while the other eye served as control.
- a formulation according to the present invention as shown in Table 11 above was tested for irritation caused to eye, as compared to the commercially available formulation, Restasis. The experiment was performed on 2 rabbits (one per composition). The formulation according to the present invention was clearly less irritating (6-8 blinks per minute with Restasis vs 2-4 for the inventive formulation). PBS (phosphate buffered saline alone) caused 1-2 blinks per minute as a control. Thus, clearly the formulation according to the present invention was much less irritating to the eye than the commercially available formulation.
- a cyclosporin such as Ciclosporin
- the term "subject” refers to the human or lower animal to whom cyclosporin was administered.
- administration may be done topically (including ophtalmically, vaginally, rectally, intranasally), orally, or parenterally, for example by intravenous drip or intraperitoneal, subcutaneous, or intramuscular injection.
- Formulations for topical administration may include but are not limited to lotions, ointments, gels, creams, suppositories, drops, liquids, sprays and powders.
- An optional but preferred formulation for administration as eye drops is described above.
- compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, sachets, capsules or tablets. Thickeners, diluents, flavorings, dispersing aids, emulsifiers or binders may be desirable. Compositions for oral administration preferably include a soft or hard gelatin capsule. Formulations for parenteral administration may include but are not limited to sterile aqueous solutions which may also contain buffers, diluents and other suitable additives.
- the formulations of the present invention may optionally be administered as a pro-nanodispersion or as a microdispersion in aqueous liquid.
- these formulations may be lyophilized (dried) after the formation of the microdispersion in aqueous liquid.
- the lyophilized (dried) dispersion is also optionally administered to the subject.
- the preferred route of administration is oral administration.
- Dosing is dependent on the severity of the symptoms and on the responsiveness of the subject to cyclosporin. Persons of ordinary skill in the art can easily determine optimum dosages, dosing methodologies and repetition rates.
- Cyclosporins are particularly noted for the treatment and prevention of organ or tissue transplant rejection, for the treatment and prevention of autoimmune disease and of inflammatory conditions, and for the treatment of multi-drug resistance (MDR).
- MDR multi-drug resistance
- the compositions of the present invention containing cyclosporin are useful for the treatment of the recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, bone-marrow, skin or corneal transplants, and in particular allogenic transplants, for example.
- the compositions of the present invention are useful for the prevention of graft- versus-host-disease, which can sometimes be seen following bone marrow transplantation.
- compositions of the present invention containing cyclosporin may be useful for the treatment of autoimmune hematological disorder (including hemolytic anemia, aplastic anemia pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary Miliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis
- autoimmune hematological disorder including hemolytic anemia, a
- compositions may be particularly useful for inflammatory conditions with an etiology including an autoimmune component such as arthritis (for example, rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases.
- arthritis for example, rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans
- rheumatic diseases for example, rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans
- the compositions of the present invention containing cyclosporin may be useful for reversing or abrogating anti- neoplastic agent resistance in tumors and the like.
- the following examples are illustrations only of methods of treating these disorders with the compositions of the present invention containing cyclosporin, and are not intended to be limiting.
- the method includes the step of administering the composition of the present invention containing cyclosporin, as described in above, to a subject to be treated.
- the composition of the present invention is administered according to an effective dosing methodology, preferably until a predefined endpoint is reached (if possible), such as the absence of symptoms of the disorder in the subject.
- the composition of the present invention may need to be administered continuously without any endpoint.
- treatment includes both pretreatment, before a pathological condition has arisen, and treatment after the condition has arisen.
- treating includes both treating the subject after the pathological condition has arisen, and preventing the development of the pathological condition.
Abstract
Description
Claims
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JP2008556913A JP2009529003A (en) | 2006-02-28 | 2007-02-28 | Pro-nanodispersion for delivering cyclosporine |
AU2007220104A AU2007220104A1 (en) | 2006-02-28 | 2007-02-28 | Pro-nanodispersion for the delivery of cyclosporin |
CA002644471A CA2644471A1 (en) | 2006-02-28 | 2007-02-28 | Pro-nanodispersion for the delivery of cyclosporin |
EP07713285A EP1988879A1 (en) | 2006-02-28 | 2007-02-28 | Pro-nanodispersion for the delivery of cyclosporin |
IL193707A IL193707A0 (en) | 2007-02-28 | 2008-08-26 | Pro-nanodispersion for the delivery of cyclosporin |
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US11/363,379 US7732404B2 (en) | 1999-12-30 | 2006-02-28 | Pro-nanodispersion for the delivery of cyclosporin |
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Publication number | Priority date | Publication date | Assignee | Title |
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US20190380958A1 (en) * | 2016-12-28 | 2019-12-19 | Chugai Seiyaku Kabushiki Kaisha | Self-emulsifying drug formulation for improving membrane permeability of compound |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE602005011928D1 (en) | 2004-01-20 | 2009-02-05 | Allergan Inc | COMPOSITIONS FOR LOCALIZED THERAPY OF THE EYE, PREFERABLY CONTAINING TRIAMCINOLONE ACETONIDE AND HYALURONIC ACID |
GB0623838D0 (en) * | 2006-11-29 | 2007-01-10 | Malvern Cosmeceutics Ltd | Novel compositions |
WO2008095122A2 (en) * | 2007-01-31 | 2008-08-07 | Bioactives, Inc. | Methods of reducing 15-f2t-isop levels in mammals |
US8101274B2 (en) * | 2007-06-11 | 2012-01-24 | Spedden Richard H | Solid state membranes with surface-embedded glycosylated amphiphilic molecules and micelles formed therefrom |
CN102176882A (en) | 2008-08-07 | 2011-09-07 | 生物活性外科公司 | Stem cell capture and immobilization coatings for medical devices and implants |
US20110033527A1 (en) * | 2009-06-02 | 2011-02-10 | Nian Wu | Opthalmic compositions of cyclosporin |
CN104080442B (en) * | 2011-11-15 | 2018-01-05 | 阿勒根公司 | The suspension of cyclosporin A form 2 |
CN108175742B (en) | 2011-11-15 | 2021-10-22 | 阿勒根公司 | Sustained action formulation of cyclosporin form 2 |
KR102072252B1 (en) | 2011-11-15 | 2020-01-31 | 알러간, 인코포레이티드 | Cyclosporin a form 2 and method of making same |
FR2988297B1 (en) * | 2012-03-22 | 2014-03-28 | Thea Lab | AQUEOUS OPHTHALMIC SOLUTION FROM CICLOSPORINE WITHOUT PRESERVATIVE |
CA2914472C (en) | 2012-08-24 | 2019-09-03 | Ashim K. Mitra | Ophthalmic formulation of polyoxyl lipid or polyoxyl fatty acid and treatment of ocular conditions |
KR101492447B1 (en) * | 2013-05-20 | 2015-02-23 | 주식회사태준제약 | Eye composition containing a cyclosporine and a method of preparing the same |
KR20160079781A (en) * | 2013-11-08 | 2016-07-06 | 액티버스 파마 컴퍼니 리미티드 | Aqueous suspension preparation comprising nanoparticles of macrolide antibacterial agent |
EP3265056A1 (en) * | 2015-03-05 | 2018-01-10 | Allergan, Inc. | Self-emulsifying drug delivery system (sedds) for ophthalmic drug delivery |
US10918694B2 (en) | 2016-02-29 | 2021-02-16 | Sun Pharma Global Fze | Topical cyclosporine-containing formulations and uses thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998007414A1 (en) * | 1996-08-22 | 1998-02-26 | Research Triangle Pharmaceuticals Ltd. | Compositions comprising microparticles of water-insoluble substances and method for preparing same |
WO2000040219A1 (en) * | 1998-12-30 | 2000-07-13 | Dexcel Ltd. | Dispersible concentrate for the delivery of cyclosporin |
WO2006001963A1 (en) * | 2004-06-09 | 2006-01-05 | Allergan, Inc. | Pharmaceutical compositions comprising cyclosporins |
Family Cites Families (254)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1274354A (en) | 1956-03-10 | 1961-10-27 | Surfactants obtained from triglycerides and polyethylene glycol | |
GB1171125A (en) | 1966-06-08 | 1969-11-19 | Glaxo Lab Ltd | Improvements in or relating to Injectable Preparations |
US3954967A (en) | 1971-08-05 | 1976-05-04 | Vanguard Chemical Company, Inc. | Method of producing microcolloidal aqueous emulsions of unsaturated organic insecticidal compounds |
US3813345A (en) | 1971-08-05 | 1974-05-28 | Vanguard Chem Co Inc | Method of producing microcolloidal aqueous emulsions of unsaturated organic compounds |
US4073943A (en) | 1974-09-11 | 1978-02-14 | Apoteksvarucentralen Vitrum Ab | Method of enhancing the administration of pharmalogically active agents |
GB1549186A (en) | 1975-10-03 | 1979-08-01 | Nat Res Dev | Optical connectors |
US4117118A (en) | 1976-04-09 | 1978-09-26 | Sandoz Ltd. | Organic compounds |
US4146499A (en) | 1976-09-18 | 1979-03-27 | Rosano Henri L | Method for preparing microemulsions |
JPS53107408A (en) | 1977-02-28 | 1978-09-19 | Yamanouchi Pharmaceut Co Ltd | Micellar preparation for rectal infusion |
FI65914C (en) | 1978-03-07 | 1984-08-10 | Sandoz Ag | FRAMEWORK FOR PHARMACEUTICAL COMPOSITION OF CYCLOSPORINE A |
US4215199A (en) | 1978-06-05 | 1980-07-29 | Sandoz Ltd. | Antibiotic production |
EP0098456B1 (en) | 1980-02-14 | 1989-05-24 | Sandoz Ag | Peptides comprising a (1s,2r,3r)- or (1r,2s,3s)-1-nitrilo-1-carbonyl-3-methyl-2-oxy-heptane or -hept-5-ene residue useful in the total synthesis of cyclosporins, and processes for their production |
FR2502951B1 (en) | 1981-04-06 | 1985-12-06 | Sandoz Sa | TOPICAL PHARMACEUTICAL COMPOSITIONS IN THE FORM OF A MICRO-EMULSION |
DE3225706C2 (en) | 1982-07-09 | 1984-04-26 | A. Nattermann & Cie GmbH, 5000 Köln | Liquid active ingredient formulations in the form of concentrates for microemulsions |
DE3237814A1 (en) | 1982-10-12 | 1984-04-12 | Warner-Lambert Co., 07950 Morris Plains, N.J. | WATER-FREE EMULSIONS AND USE THEREOF |
SE8301182D0 (en) | 1983-03-04 | 1983-03-04 | Haessle Ab | NOVEL COMPOUNDS |
US4731384A (en) | 1983-07-01 | 1988-03-15 | Troponwerke Gmbh & Co, Kg | Etofenamate formulation |
JPS6061535A (en) | 1983-08-24 | 1985-04-09 | エフ・ホフマン・ラ・ロシユ・ウント・コンパニ−・アクチエンゲゼルシヤフト | Pharmaceutical composition |
DE3406497A1 (en) | 1984-02-23 | 1985-09-05 | Mueller Bernhard Willi Werner | HIGHLY DISPERSAL PHARMACEUTICAL MULTI-COMPONENT SYSTEMS AND METHOD FOR THEIR PRODUCTION |
US4713246A (en) | 1984-03-19 | 1987-12-15 | Bristol-Myers Company | Etoposide oral dosage form |
US4794000A (en) | 1987-01-08 | 1988-12-27 | Synthetic Blood Corporation | Coacervate-based oral delivery system for medically useful compositions |
US4963367A (en) | 1984-04-27 | 1990-10-16 | Medaphore, Inc. | Drug delivery compositions and methods |
US4572915A (en) | 1984-05-01 | 1986-02-25 | Bioglan Laboratories | Clear micellized solutions of fat soluble essential nutrients |
US4871768A (en) | 1984-07-12 | 1989-10-03 | New England Deaconess Hospital Corporation | Dietary supplement utilizing ω-3/medium chain trigylceride mixtures |
US5639724A (en) | 1984-07-24 | 1997-06-17 | Sandoz Ltd. | Cyclosporin galenic forms |
EP0170623B1 (en) | 1984-08-02 | 1990-11-28 | Sandoz Ag | Novel pharmaceutical use of (nva)2-cyclosporine |
JPS6150978A (en) | 1984-08-16 | 1986-03-13 | Takeda Chem Ind Ltd | Pyridine derivative and preparation thereof |
DE3500103A1 (en) | 1985-01-04 | 1986-07-10 | R.P. Scherer GmbH, 6930 Eberbach | PHARMACEUTICAL PREPARATION WITH AN INTENSIVE SOLUTION IN WATER AND DIGESTIVE JUICES |
US4885172A (en) | 1985-06-26 | 1989-12-05 | The Liposome Company, Inc. | Composition for targeting, storing and loading of liposomes |
US5171578A (en) | 1985-06-26 | 1992-12-15 | The Liposome Company, Inc. | Composition for targeting, storing and loading of liposomes |
IL78929A0 (en) | 1985-07-29 | 1986-09-30 | Abbott Lab | Microemulsion compositions for parenteral administration |
US4753963A (en) | 1985-09-26 | 1988-06-28 | The Procter & Gamble Company | Nutritional fat suitable for enteral and parenteral products |
US4861580A (en) | 1985-10-15 | 1989-08-29 | The Liposome Company, Inc. | Composition using salt form of organic acid derivative of alpha-tocopheral |
US5041278A (en) | 1985-10-15 | 1991-08-20 | The Liposome Company, Inc. | Alpha tocopherol-based vesicles |
US4797272A (en) | 1985-11-15 | 1989-01-10 | Eli Lilly And Company | Water-in-oil microemulsions for cosmetic uses |
CA1327010C (en) | 1986-02-13 | 1994-02-15 | Tadashi Makino | Stabilized solid pharmaceutical composition containing antiulcer benzimidazole compound and its production |
GB2189699A (en) | 1986-04-30 | 1987-11-04 | Haessle Ab | Coated acid-labile medicaments |
SE457693B (en) | 1986-07-01 | 1989-01-23 | Drilletten Ab | COMPOSITION WITH REGULATED RELEASE WAS A BIOLOGICAL MATERIAL LOST OR DISPERSED IN AN L2 PHASE |
EP0256856A3 (en) | 1986-08-14 | 1989-01-11 | Synthetic Blood Corporation | A parenterally administrable composition |
DE3629386A1 (en) | 1986-08-29 | 1988-03-03 | Scherer Gmbh R P | GELATINE CAPSULES AND METHOD FOR THEIR PRODUCTION |
US5071643A (en) | 1986-10-17 | 1991-12-10 | R. P. Scherer Corporation | Solvent system enhancing the solubility of pharmaceuticals for encapsulation |
GB8630273D0 (en) | 1986-12-18 | 1987-01-28 | Til Medical Ltd | Pharmaceutical delivery systems |
US5154930A (en) | 1987-03-05 | 1992-10-13 | The Liposome Company, Inc. | Pharmacological agent-lipid solution preparation |
DE3707711A1 (en) | 1987-03-11 | 1988-09-22 | Hoechst Ag | OIL-IN-WATER EMULSIONS, METHOD FOR THEIR PRODUCTION AND THEIR USE |
CA1301642C (en) | 1987-03-30 | 1992-05-26 | Howard Bernard Dawson | Chemical formulations |
KR880012221A (en) | 1987-04-13 | 1988-11-26 | 사노 가즈오 | Pharmaceutical compositions containing esters or amides as active ingredients |
US4798823A (en) | 1987-06-03 | 1989-01-17 | Merck & Co., Inc. | New cyclosporin analogs with modified "C-9 amino acids" |
JP2577049B2 (en) | 1987-06-04 | 1997-01-29 | 三共株式会社 | Cyclosporine preparation |
ATE95193T1 (en) | 1987-06-17 | 1993-10-15 | Sandoz Ag | CYCLOSPORINS AND THEIR USE AS MEDICINAL PRODUCTS. |
GB2206119B (en) | 1987-06-22 | 1990-10-31 | Merck & Co Inc | A new cyclosporin derivative with modified "8-amino acid" |
US4835002A (en) | 1987-07-10 | 1989-05-30 | Wolf Peter A | Microemulsions of oil in water and alcohol |
US4963362A (en) | 1987-08-07 | 1990-10-16 | Regents Of The University Of Minnesota | Freeze-dried liposome mixture containing cyclosporin |
US5756450A (en) | 1987-09-15 | 1998-05-26 | Novartis Corporation | Water soluble monoesters as solubilisers for pharmacologically active compounds and pharmaceutical excipients and novel cyclosporin galenic forms |
HU205010B (en) | 1987-09-15 | 1992-03-30 | Sandoz Ag | Process for producing pharmaceutical compositions comprising compounds soluble up to 1 per cent and having medical activity |
GB8729153D0 (en) | 1987-12-14 | 1988-01-27 | Efamol Ltd | Fatty acid compositions |
US5244925A (en) | 1987-12-18 | 1993-09-14 | Kabi Pharmacia Aktiebolag | Emulsion for parenteral administration |
HU203564B (en) | 1987-12-21 | 1991-08-28 | Sandoz Ag | Process for producing new orthorombos cyclosporin without solvatation |
US5081105A (en) | 1988-01-15 | 1992-01-14 | New England Deaconess Hospital Corporation | Method of treating cancer using structured lipids |
US4904474A (en) | 1988-01-25 | 1990-02-27 | Alza Corporation | Delivery of drug to colon by oral disage form |
AU609242B2 (en) | 1988-01-29 | 1991-04-26 | Novartis Ag | Cyclosporin compositions |
US4994267A (en) | 1988-03-04 | 1991-02-19 | Noven Pharmaceuticals, Inc. | Transdermal acrylic multipolymer drug delivery system |
WO1991014463A1 (en) | 1990-03-28 | 1991-10-03 | Noven Pharmaceuticals, Inc. | Method and device for the release of drugs to the skin |
US5656286A (en) | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
US4814168A (en) | 1988-03-04 | 1989-03-21 | Noven Pharmaceuticals, Inc. | Transdermal multipolymer drug delivery system |
GB8809616D0 (en) | 1988-04-22 | 1988-05-25 | Cancer Res Campaign Tech | Further improvements relating to drug delivery systems |
JP2677613B2 (en) | 1988-06-24 | 1997-11-17 | エーザイ株式会社 | Absorption promoting composition of vitamin E or derivative thereof |
HU201567B (en) | 1988-07-21 | 1990-11-28 | Gyogyszerkutato Intezet | Process for production of intravenous medical compositions containing cyclosphorin |
US5350741A (en) | 1988-07-30 | 1994-09-27 | Kanji Takada | Enteric formulations of physiologically active peptides and proteins |
US6007840A (en) | 1988-09-16 | 1999-12-28 | Novartis Ag | Pharmaceutical compositions comprising cyclosporins |
KR0148748B1 (en) | 1988-09-16 | 1998-08-17 | 장 크라메르, 한스 루돌프 하우스 | A multiphase cyclosporin composition |
US5342625A (en) | 1988-09-16 | 1994-08-30 | Sandoz Ltd. | Pharmaceutical compositions comprising cyclosporins |
GB8822857D0 (en) | 1988-09-29 | 1988-11-02 | Patralan Ltd | Pharmaceutical formulations |
KR900004323A (en) | 1988-09-29 | 1990-04-12 | 후쿠하라 요시하루 | Emulsifying composition |
SE8804164A0 (en) | 1988-11-17 | 1990-05-18 | Per Prisell | Pharmaceutical preparation |
HU201577B (en) | 1988-12-20 | 1990-11-28 | Gyogyszerkutato Intezet | Process for producing cyclosporin antibiotics |
US4994439A (en) | 1989-01-19 | 1991-02-19 | California Biotechnology Inc. | Transmembrane formulations for drug administration |
US4996193A (en) | 1989-03-03 | 1991-02-26 | The Regents Of The University Of California | Combined topical and systemic method of administration of cyclosporine |
US5272068A (en) | 1989-03-15 | 1993-12-21 | Merck & Co., Inc. | Process for producing immunosuppressant agent L-683942 by fermentation |
DE69013189T2 (en) | 1989-03-15 | 1995-05-11 | Merck & Co Inc | Method for producing an immunosuppressive substance (demethimmunomycin) by using a strain mutant of a microorganism. |
AU614465B2 (en) | 1989-04-05 | 1991-08-29 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Medicinal emulsions |
US5364632A (en) | 1989-04-05 | 1994-11-15 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Medicinal emulsions |
DE3919982A1 (en) | 1989-06-19 | 1990-12-20 | Liedtke Pharmed Gmbh | ORAL LIPID MEDICINE FORM |
US5532002A (en) | 1989-08-17 | 1996-07-02 | Cortecs Limited | Gelatin pharmaceutical formulations |
DK469989D0 (en) | 1989-09-22 | 1989-09-22 | Bukh Meditec | PHARMACEUTICAL PREPARATION |
IE904098A1 (en) | 1989-11-13 | 1991-05-22 | Nova Pharm Corp | Lipospheres for controlled delivery of substances |
US5188837A (en) | 1989-11-13 | 1993-02-23 | Nova Pharmaceutical Corporation | Lipsopheres for controlled delivery of substances |
DK0502119T3 (en) | 1989-11-13 | 1996-06-03 | Abraham J Domb | Lipospheres for controlled release of substances |
US5227165A (en) | 1989-11-13 | 1993-07-13 | Nova Pharmaceutical Corporation | Liposphere delivery systems for local anesthetics |
JP2785981B2 (en) | 1989-11-20 | 1998-08-13 | 株式会社資生堂 | Emulsion composition |
US5178866A (en) | 1990-03-23 | 1993-01-12 | Alza Corporation | Dosage form for delivering drug to the intestine |
US5091188A (en) | 1990-04-26 | 1992-02-25 | Haynes Duncan H | Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs |
IL98087A (en) | 1990-05-04 | 1996-11-14 | Perio Prod Ltd | Colonic drug delivery system |
WO1992003121A1 (en) | 1990-08-13 | 1992-03-05 | Yesair David W | Mixed lipid-bicarbonate colloidal particles for delivering drugs or calories |
US5227298A (en) | 1990-08-17 | 1993-07-13 | The Trustees Of Columbia University In The City Of New York | Method for microencapuslation of cells or tissue |
US5156850A (en) | 1990-08-31 | 1992-10-20 | Alza Corporation | Dosage form for time-varying patterns of drug delivery |
US5665379A (en) | 1990-09-28 | 1997-09-09 | Pharmacia & Upjohn Aktiebolag | Lipid particle forming matrix, preparation and use thereof |
DE69124459T3 (en) | 1990-11-02 | 2001-05-31 | Novartis Ag | Cyclosporine |
AU665931B2 (en) | 1990-11-06 | 1996-01-25 | Nippon Shinyaku Co. Ltd. | Lyophilized preparation and production thereof |
HU208491B (en) | 1990-11-27 | 1993-11-29 | Gyogyszerkutato Intezet | Process for producing oral pharmaceutical composition containing cyclosporin |
NL9100038A (en) | 1991-01-11 | 1992-08-03 | Stamicarbon | ENZYME-CATALYZED PREPARATION OF OPTICALLY ACTIVE CARBONIC ACIDS. |
US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
DE69222150T2 (en) | 1991-01-25 | 1998-01-15 | Fujisawa Pharmaceutical Co | PROCESS FOR THE PRODUCTION OF CYCLOSPORIN-A AND / OR C |
CZ2190U1 (en) | 1991-02-01 | 1994-07-14 | Alexandr Rndr. Csc. Jegorov | Targeted polymeric cyclosporin conjugates |
US5300529A (en) | 1991-02-12 | 1994-04-05 | Isp Investments Inc. | Stable, clear, efficacious aqueous microemulsion compositions containing a high loading of a water-insoluble, agriculturally active chemical |
US5378475A (en) | 1991-02-21 | 1995-01-03 | University Of Kentucky Research Foundation | Sustained release drug delivery devices |
US5171217A (en) | 1991-02-28 | 1992-12-15 | Indiana University Foundation | Method for delivery of smooth muscle cell inhibitors |
ES2078374T3 (en) | 1991-04-06 | 1995-12-16 | Dresden Arzneimittel | PROCEDURE FOR THE PRODUCTION BY FERMENTATION AND ISOLATION OF CYCLOSPORINE A, AND NEW STRAINS FORMING CYCLOSPORIN. |
ES2136620T3 (en) | 1991-04-19 | 1999-12-01 | Lds Technologies Inc | CONVERTIBLE MICROEMULSION FORMULATIONS. |
US5683714A (en) | 1991-04-19 | 1997-11-04 | Nexstar Pharmaceuticals, Inc. | Liposomal cyclosporin pharmaceutical formulation |
DE69211691T2 (en) | 1991-04-19 | 1997-01-16 | Nexstar Pharmaceuticals Inc | PHARMACEUTICAL FORMULATION AND PHARMACEUTICAL PROCEDURE |
ATE156707T1 (en) | 1991-06-21 | 1997-08-15 | Ilsan Ilac Ve Hammaddeleri San | NEW GALENIC PROCESS FOR PELLETS CONTAINING OMEPRAZOLE |
GB9113872D0 (en) | 1991-06-27 | 1991-08-14 | Sandoz Ag | Improvements in or relating to organic compounds |
US5545423A (en) | 1991-11-25 | 1996-08-13 | Vivorx, Inc. | Cytoprotective, biocompatible, retrievable macrocapsule containment systems for biologically active materials |
US5206219A (en) | 1991-11-25 | 1993-04-27 | Applied Analytical Industries, Inc. | Oral compositions of proteinaceous medicaments |
US5614219A (en) | 1991-12-05 | 1997-03-25 | Alfatec-Pharma Gmbh | Oral administration form for peptide pharmaceutical substances, in particular insulin |
IL101007A (en) | 1992-02-18 | 1997-08-14 | Pharmos Ltd | Dry stable compositions prepared by lyophilization |
SE9200951D0 (en) | 1992-03-27 | 1992-03-27 | Kabi Pharmacia Ab | PHARMACEUTICAL COMPOSITION CONTAINING A DEFINED LIPID SYSTEM |
US5637317A (en) | 1992-05-18 | 1997-06-10 | Dietl; Hans | Pharmaceutical preparation containing cyclosporin(s) for oral administration and process for producing same |
US5529785A (en) | 1993-05-12 | 1996-06-25 | Dietl; Hans | Pharmaceutical preparation containing cyclosporin(s) for oral administration and process for producing same |
HU213553B (en) | 1992-05-25 | 1997-07-28 | Biogal Gyogyszergyar | Process for isolating of cyclosporin-a |
IT1260505B (en) | 1992-06-01 | 1996-04-09 | Poli Ind Chimica Spa | ORAL PHARMACEUTICAL SYSTEMS WITH DELAYED DELIVERY FOR THE SPECIFIC RELEASE IN THE COLON |
GB9213874D0 (en) | 1992-06-30 | 1992-08-12 | Fisons Plc | Process to novel medicament form |
IT1255449B (en) | 1992-06-30 | 1995-10-31 | Fabio Berlati | USE OF NOR- AND HOMO-DERIVATIVES OF BILE ACIDS AS DRUGS ABSORPTION PROMOTERS. |
US5759566A (en) | 1992-07-28 | 1998-06-02 | Poli Industria Chimica Spa | Microemulsion pharmaceutical compositions for the delivery of pharmaceutically active agents |
DK0616802T3 (en) | 1992-08-13 | 1998-10-19 | Teikoku Seiyaku Kk | Oral preparation for release into the lower digestive tract |
CZ278863B6 (en) | 1992-09-07 | 1994-07-13 | Galena | Medicinal preparations with n-methylated cyclic undecapeptides |
JP3756512B2 (en) | 1992-09-21 | 2006-03-15 | ファルマシア・アンド・アップジョン・カンパニー・エルエルシー | Sustained release protein preparation |
PT589843E (en) | 1992-09-25 | 2002-04-29 | Novartis Ag | PHARMACEUTICAL COMPOSITIONS CONTAINING CYCLOSPORTS |
WO1994009898A1 (en) | 1992-10-26 | 1994-05-11 | Schwarz Pharma Ag | Method of manufacturing microcapsules |
IT1256386B (en) | 1992-11-13 | 1995-12-04 | Luigi Boltri | PHARMACEUTICAL COMPOSITIONS INCLUDING A DRUG, A CROSS-LINKED POLYMERIC SUBSTANCE, AN OIL AND A SURFACTIVE AGENT |
JP3520517B2 (en) | 1992-11-18 | 2004-04-19 | 藤沢薬品工業株式会社 | Sustained pharmaceutical preparations |
US5376688A (en) | 1992-12-18 | 1994-12-27 | R. P. Scherer Corporation | Enhanced solubility pharmaceutical solutions |
FI92334C (en) | 1992-12-30 | 1994-10-25 | Leiras Oy | Process for producing cyclosporins and new Tolypocladium strain useful in the process |
AU683027B2 (en) | 1993-01-27 | 1997-10-30 | Scotia Holdings Plc | Triglycerides |
AU6268894A (en) | 1993-02-22 | 1994-09-14 | Alza Corporation | Compositions for oral delivery of active agents |
US5686105A (en) | 1993-10-19 | 1997-11-11 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
CA2120197A1 (en) | 1993-04-02 | 1994-10-03 | Kenji Endo | Stable aqueous dispersions containing liposomes |
JP3119540B2 (en) | 1993-04-12 | 2000-12-25 | 松下電器産業株式会社 | Light tap |
DE69431310T2 (en) | 1993-04-19 | 2003-05-22 | Inst Advanced Skin Res Inc | MICROEMULSION PREPARATION CONTAINING A HEAVY ABSORBABLE SUBSTANCE |
DK0695177T3 (en) | 1993-04-20 | 1998-09-28 | Hexal Ag | Patch containing active substance |
DE4338086A1 (en) | 1993-11-08 | 1995-05-11 | Dietl Hans | Cyclosporin (e) containing pharmaceutical preparation for oral administration and process for their preparation |
US5576016A (en) | 1993-05-18 | 1996-11-19 | Pharmos Corporation | Solid fat nanoemulsions as drug delivery vehicles |
CH686761A5 (en) | 1993-05-27 | 1996-06-28 | Sandoz Ag | Pharmaceutical formulations. |
GB2278780B (en) | 1993-05-27 | 1998-10-14 | Sandoz Ltd | Macrolide formulations |
US5593691A (en) | 1993-06-03 | 1997-01-14 | Marigen S.A. | Biotenside solvents for pharmaceuticals and cosmetics |
US5478860A (en) | 1993-06-04 | 1995-12-26 | Inex Pharmaceuticals Corp. | Stable microemulsions for hydrophobic compound delivery |
US5639474A (en) | 1993-07-01 | 1997-06-17 | Hanmi Pharm. Ind., Ltd. | Cyclosporin soft capsule composition |
DE4322826A1 (en) | 1993-07-08 | 1995-01-12 | Galenik Labor Freiburg Gmbh | Pharmaceutical preparation |
CA2144996C (en) | 1993-07-16 | 2004-09-07 | Jefferson E. Odhner | Diffractive display utilizing reflective or transmissive light yielding single pixel full color capability |
ES2068762B1 (en) | 1993-07-21 | 1995-12-01 | Lipotec Sa | A NEW PHARMACEUTICAL PREPARATION TO IMPROVE THE BIOAVAILABILITY OF DRUGS OF DIFFICULT ABSORPTION AND PROCEDURE FOR THEIR OBTAINING. |
IL110787A0 (en) | 1993-08-27 | 1994-11-11 | Sandoz Ag | Biodegradable polymer, its preparation and pharmaceutical composition containing it |
EP1029538A3 (en) | 1993-09-28 | 2003-10-15 | R.P. Scherer GmbH | Soft gelatin capsule manufacture |
DE10199039I2 (en) | 1993-10-22 | 2008-08-07 | Hexal Ag Ind 25 | PHARMACEUTICAL COMPOSITION WITH CYCLOSPORIN A, A VITAMIN DERIVATIVE AND AN EMULSIFIER |
US6022852A (en) | 1993-10-22 | 2000-02-08 | Hexal Ag | Pharmaceutical composition containing cyclosporin A |
IL107471A (en) | 1993-11-02 | 1997-09-30 | Yissum Res Dev Co | Pharmaceutical preparation comprising a self- emulsifying formulation and process for its production |
CA2176927C (en) | 1993-11-17 | 2010-03-23 | Seang H. Yiv | Transparent liquid for encapsulated drug delivery |
DE4340781C3 (en) | 1993-11-30 | 2000-01-27 | Novartis Ag | Liquid preparations containing cyclosporin and process for their preparation |
DE4402867C1 (en) | 1994-01-31 | 1995-06-14 | Rentschler Arzneimittel | Liposome(s) contg. encapsulated protein for pharmaceutical or cosmetic use |
US5567592A (en) | 1994-02-02 | 1996-10-22 | Regents Of The University Of California | Screening method for the identification of bioenhancers through the inhibition of P-glycoprotein transport in the gut of a mammal |
CA2182575C (en) | 1994-02-04 | 2000-11-28 | Anders Carlsson | Oil-in-water emulsions |
US5891846A (en) | 1994-02-17 | 1999-04-06 | Shiseido Company, Ltd. | Cyclosporin-containing emulsion composition |
KR0146671B1 (en) | 1994-02-25 | 1998-08-17 | 김충환 | Cyclosporin-containing powder composition |
KR970701551A (en) | 1994-03-11 | 1997-04-12 | 고야 마사시 | Liposomal Preparation (LIPOSOME PREPARATION) |
GB9405304D0 (en) | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
US5430021A (en) | 1994-03-18 | 1995-07-04 | Pharmavene, Inc. | Hydrophobic drug delivery systems |
US5731356A (en) | 1994-03-22 | 1998-03-24 | Zeneca Limited | Pharmaceutical compositions of propofol and edetate |
US5651980A (en) | 1994-04-15 | 1997-07-29 | Biohybrid Technologies, Inc. | Methods of use of uncoated gel particles |
DE4417851C1 (en) | 1994-05-20 | 1995-10-05 | Horst Heirler | Dietary food with medium-chain fatty acids and its use |
FI100692B (en) | 1994-05-24 | 1998-02-13 | Leiras Oy | A process for the preparation of pharmaceutical compositions, wherein the compositions are based on microemulsion gels and new gels directed to microemulsions. |
ES2137516T3 (en) | 1994-06-01 | 1999-12-16 | Yuhan Corp | COMPOSITION BASED ON CYCLOSPORINE AND ITS MANUFACTURING PROCEDURE. |
US5958458A (en) | 1994-06-15 | 1999-09-28 | Dumex-Alpharma A/S | Pharmaceutical multiple unit particulate formulation in the form of coated cores |
US5817320A (en) | 1994-06-20 | 1998-10-06 | The United States Of America As Represented By The Secretary Of The Agriculture | In ovo immunization of avian embryos with oil-emulsion vaccines |
US5536507A (en) | 1994-06-24 | 1996-07-16 | Bristol-Myers Squibb Company | Colonic drug delivery system |
GB2290965A (en) | 1994-07-11 | 1996-01-17 | Therapicon Srl | Multiple layer capsules for drugs |
EP0697214A1 (en) | 1994-07-19 | 1996-02-21 | Vestar, Inc. | Liposomal cyclosporin pharmaceutical formulations |
US5616330A (en) | 1994-07-19 | 1997-04-01 | Hemagen/Pfc | Stable oil-in-water emulsions incorporating a taxine (taxol) and method of making same |
US5599534A (en) | 1994-08-09 | 1997-02-04 | University Of Nebraska | Reversible gel-forming composition for sustained delivery of bio-affecting substances, and method of use |
US5733575A (en) | 1994-10-07 | 1998-03-31 | Bpsi Holdings, Inc. | Enteric film coating compositions, method of coating therewith, and coated forms |
KR100304324B1 (en) | 1994-10-13 | 2001-11-22 | 김용규 | Method for manufacturing cyclosporine a |
KR0126610B1 (en) | 1994-10-18 | 1997-12-29 | 김충환 | Producing method of cyclosporina by cell fusioned microorganism |
US5603951A (en) | 1994-11-09 | 1997-02-18 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule compositions |
DE4440337A1 (en) | 1994-11-11 | 1996-05-15 | Dds Drug Delivery Services Ges | Pharmaceutical nanosuspensions for drug application as systems with increased saturation solubility and dissolution rate |
HU215966B (en) | 1994-11-21 | 1999-07-28 | BIOGAL Gyógyszergyár Rt. | Oral multiple emulsion-preconcentrate containing cyclosporin |
DE4446470A1 (en) | 1994-12-23 | 1996-06-27 | Basf Ag | Process for the production of dividable tablets |
KR0167613B1 (en) | 1994-12-28 | 1999-01-15 | 한스 루돌프 하우스, 니콜 케르커 | Cyclosporin-containing soft capsule compositions |
US5608278A (en) | 1995-01-13 | 1997-03-04 | Eastman Kodak Company | Self-pumped fluid bearing with electromagnetic levitation such as for a light beam deflector |
EP0725076B1 (en) | 1995-02-01 | 2001-06-06 | National Research Development Corporation of India | A process for the preparation of cyclosporin A from tolypocladium species |
US5571536A (en) | 1995-02-06 | 1996-11-05 | Nano Systems L.L.C. | Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids |
US5560931A (en) | 1995-02-14 | 1996-10-01 | Nawosystems L.L.C. | Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids |
SE9500478D0 (en) | 1995-02-09 | 1995-02-09 | Astra Ab | New pharmaceutical formulation and process |
US5573783A (en) | 1995-02-13 | 1996-11-12 | Nano Systems L.L.C. | Redispersible nanoparticulate film matrices with protective overcoats |
FI102758B (en) | 1995-03-03 | 1999-02-15 | Santen Pharmaceutical Co Ltd | Process for producing pure cyclosporine form |
JP2740153B2 (en) | 1995-03-07 | 1998-04-15 | エフ・ホフマン−ラ ロシユ アーゲー | Mixed micelle |
US6004583A (en) | 1995-03-22 | 1999-12-21 | Orex Pharmaceutical Development Corp. | Protein-containing polymer composition for oral administration |
IE75744B1 (en) | 1995-04-03 | 1997-09-24 | Elan Corp Plc | Controlled release biodegradable micro- and nanospheres containing cyclosporin |
WO1996033697A1 (en) | 1995-04-24 | 1996-10-31 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Self-emulsifiable formulation producing an oil-in-water emulsion |
US5653987A (en) | 1995-05-16 | 1997-08-05 | Modi; Pankaj | Liquid formulations for proteinic pharmaceuticals |
US5686106A (en) | 1995-05-17 | 1997-11-11 | The Procter & Gamble Company | Pharmaceutical dosage form for colonic delivery |
US5726181A (en) | 1995-06-05 | 1998-03-10 | Bionumerik Pharmaceuticals, Inc. | Formulations and compositions of poorly water soluble camptothecin derivatives |
US5656287A (en) | 1995-06-07 | 1997-08-12 | Nexstar Pharmaceuticals, Inc. | Liposomal cyclosporin formulations as agents for immunosuppression and multiple drug resistant indications |
US5716928A (en) | 1995-06-07 | 1998-02-10 | Avmax, Inc. | Use of essential oils to increase bioavailability of oral pharmaceutical compounds |
US5665386A (en) | 1995-06-07 | 1997-09-09 | Avmax, Inc. | Use of essential oils to increase bioavailability of oral pharmaceutical compounds |
US5616595A (en) | 1995-06-07 | 1997-04-01 | Abbott Laboratories | Process for recovering water insoluble compounds from a fermentation broth |
US5962019A (en) | 1995-08-25 | 1999-10-05 | Sangstat Medical Corporation | Oral cyclosporin formulations |
US5827822A (en) | 1996-03-25 | 1998-10-27 | Sangstat Medical Corporation | Cyclosporin a formulations as nanoparticles |
US5766629A (en) | 1995-08-25 | 1998-06-16 | Sangstat Medical Corporation | Oral cyclosporin formulations |
EP0760237A1 (en) | 1995-08-30 | 1997-03-05 | Cipla Limited | Oil-in-water microemulsions |
US5968972A (en) | 1995-10-26 | 1999-10-19 | Baker Norton Pharmaceuticals, Inc. | Method for increasing the oral bioactivity of pharmaceutical agents |
NZ280689A (en) | 1995-12-15 | 1997-08-22 | Bernard Charles Sherma Sherman | Pharmaceutical composition comprising a cyclosporipharmaceutical composition comprising a cyclosporin; a tocol, tocopherol or tocotrienol; and propylen; a tocol, tocopherol or tocotrienol; and propylene carbonate or polyethylene glycol ne carbonate or polyethylene glycol |
CZ288631B6 (en) | 1996-01-18 | 2001-08-15 | Galena, A. S. | Therapeutic preparations containing cyclosporin |
US5858401A (en) | 1996-01-22 | 1999-01-12 | Sidmak Laboratories, Inc. | Pharmaceutical composition for cyclosporines |
DE69728802T2 (en) | 1996-02-05 | 2005-03-31 | Handa, Hiroshi, Prof. | Active ingredient immobilized particles and methods for purifying proteins |
KR970064620A (en) | 1996-03-05 | 1997-10-13 | 임성기 | Cyclosporin-containing external-use pharmaceutical composition |
DE19611094C2 (en) | 1996-03-21 | 1999-06-17 | Dresden Arzneimittel | Process for the purification of cyclosporin A and / or related cyclosporins from a cyclosporin-containing crude extract using chromatographic processes using silica gel as the adsorbent |
SE507682C2 (en) | 1996-03-29 | 1998-07-06 | Marcin Krotkiewski | Pharmaceutical preparation for the treatment of gastritis, reflux oesophagitis, duodenitis, dyspepsia and peptic ulcer disease containing a mixture of ammonium bismuth citrate and an alginate |
IL117773A (en) | 1996-04-02 | 2000-10-31 | Pharmos Ltd | Solid lipid compositions of coenzyme Q10 for enhanced oral bioavailability |
US5660858A (en) | 1996-04-03 | 1997-08-26 | Research Triangle Pharmaceuticals | Cyclosporin emulsions |
US6030941A (en) | 1996-05-01 | 2000-02-29 | Avi Biopharma, Inc. | Polymer composition for delivering substances in living organisms |
US5747330A (en) | 1996-06-05 | 1998-05-05 | Poli Industria Chimica | Antibiotic producing microbe |
US5709797A (en) | 1996-06-05 | 1998-01-20 | Poli Industria Chimica S.P.A. | Method of isolating cyclosporins |
EP0914132A1 (en) | 1996-06-11 | 1999-05-12 | Cellena Ag | Eutrophic drug compositions based on transferrin glycans |
US5958876A (en) | 1996-06-19 | 1999-09-28 | Novartis Ag | Cyclosporin-containing pharmaceutical compositions |
US5958378A (en) | 1996-07-03 | 1999-09-28 | Research Development Foundation | High dose liposomal aerosol formulations containing cyclosporin A or budesonide |
DE19629753A1 (en) | 1996-07-23 | 1998-01-29 | Basf Ag | Process for the production of solid dosage forms |
KR980008239A (en) | 1996-07-26 | 1998-04-30 | 김충환 | Cyclosporin-containing pharmaceutical composition |
CZ267796A3 (en) | 1996-09-12 | 1998-04-15 | Galena A.S. | Medicamentous preparations, particularly for internal application in the form of inherently micro-emulsifying therapeutical systems |
US5798333A (en) | 1996-09-17 | 1998-08-25 | Sherman; Bernard C. | Water-soluble concentrates containing cyclosporins |
DK0951280T3 (en) | 1996-10-03 | 2004-05-17 | Hermes Biosciences Inc | Hydrophilic microparticles and processes for their preparation |
AU6014098A (en) | 1996-12-31 | 1998-07-31 | Inhale Therapeutic Systems | Aerosolized hydrophobic drug |
JP3632183B2 (en) * | 1997-01-28 | 2005-03-23 | 東洋電装株式会社 | Discharge lamp unit |
US6051257A (en) | 1997-02-24 | 2000-04-18 | Superior Micropowders, Llc | Powder batch of pharmaceutically-active particles and methods for making same |
HU228855B1 (en) | 1997-03-12 | 2013-06-28 | Abbott Lab | Hydrophilic binary systems for the administration of cyclosporine |
DE19710213A1 (en) | 1997-03-12 | 1998-09-17 | Basf Ag | Process for the manufacture of solid combination dosage forms |
DE19720312A1 (en) | 1997-05-15 | 1998-11-19 | Hoechst Ag | Preparation with increased in vivo tolerance |
JPH1169867A (en) * | 1997-08-11 | 1999-03-09 | Matsushita Electric Ind Co Ltd | Device and method for controlling and driving sensorless dc brushless motor |
US5962522A (en) | 1997-09-05 | 1999-10-05 | Avmax, Inc. | Propyl gallate to increase bioavailability of orally administered pharmaceutical compounds |
US6008191A (en) | 1997-09-08 | 1999-12-28 | Panacea Biotec Limited | Pharmaceutical compositions containing cyclosporin |
US6010719A (en) | 1997-09-16 | 2000-01-04 | Universiteit Gent | Freeze-dried disintegrating tablets |
NZ328751A (en) | 1997-09-16 | 1999-01-28 | Bernard Charles Sherman | Solid medicament containing an anionic surfactant and cyclosporin |
US6004573A (en) | 1997-10-03 | 1999-12-21 | Macromed, Inc. | Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
US6027747A (en) | 1997-11-11 | 2000-02-22 | Terracol; Didier | Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions |
US5891845A (en) | 1997-11-21 | 1999-04-06 | Fuisz Technologies Ltd. | Drug delivery systems utilizing liquid crystal structures |
US6063762A (en) | 1997-12-05 | 2000-05-16 | Chong Kun Dang Corp. | Cyclosporin-containing microemulsion preconcentrate composition |
US6028067A (en) | 1997-12-05 | 2000-02-22 | Chong Kun Dang Corp. | Cyclosporin-containing microemulsion preconcentrate composition |
US6013665A (en) | 1997-12-16 | 2000-01-11 | Abbott Laboratories | Method for enhancing the absorption and transport of lipid soluble compounds using structured glycerides |
FR2780061B1 (en) | 1998-06-22 | 2001-09-07 | Rhone Poulenc Rorer Sa | NOVEL PROCESS FOR THE PREPARATION OF CYCLOSPORIN DERIVATIVES |
US6051607A (en) | 1998-07-02 | 2000-04-18 | Micro Therapeutics, Inc. | Vascular embolizing compositions comprising ethyl lactate and methods for their use |
EP1018340B1 (en) | 1999-01-06 | 2003-09-10 | Tecnimede-Sociedade Tecnico-Medicinal, S.A. | Inclusion aminoacid salts compounds of benzimidazole derivatives with cyclodextrins, their preparation and pharmaceutical formulations containing them |
US6267985B1 (en) | 1999-06-30 | 2001-07-31 | Lipocine Inc. | Clear oil-containing pharmaceutical compositions |
US6045826A (en) | 1999-04-02 | 2000-04-04 | National Research Council Of Canada | Water-soluble compositions of bioactive lipophilic compounds |
US6057289A (en) | 1999-04-30 | 2000-05-02 | Pharmasolutions, Inc. | Pharmaceutical composition comprising cyclosporin in association with a carrier in a self-emulsifying drug delivery system |
US6388789B1 (en) | 2000-09-19 | 2002-05-14 | The Charles Stark Draper Laboratory, Inc. | Multi-axis magnetically actuated device |
AU2001292953A1 (en) * | 2000-09-22 | 2002-04-02 | U.S. Monolithics, L.L.C. | Mmic folded power amplifier |
WO2003000295A2 (en) | 2001-06-21 | 2003-01-03 | Pfizer Products Inc. | Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors |
-
2006
- 2006-02-28 US US11/363,379 patent/US7732404B2/en not_active Expired - Fee Related
-
2007
- 2007-02-28 WO PCT/IL2007/000264 patent/WO2007099537A1/en active Application Filing
- 2007-02-28 JP JP2008556913A patent/JP2009529003A/en active Pending
- 2007-02-28 AU AU2007220104A patent/AU2007220104A1/en not_active Abandoned
- 2007-02-28 CA CA002644471A patent/CA2644471A1/en not_active Abandoned
- 2007-02-28 EP EP07713285A patent/EP1988879A1/en not_active Ceased
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998007414A1 (en) * | 1996-08-22 | 1998-02-26 | Research Triangle Pharmaceuticals Ltd. | Compositions comprising microparticles of water-insoluble substances and method for preparing same |
WO2000040219A1 (en) * | 1998-12-30 | 2000-07-13 | Dexcel Ltd. | Dispersible concentrate for the delivery of cyclosporin |
WO2006001963A1 (en) * | 2004-06-09 | 2006-01-05 | Allergan, Inc. | Pharmaceutical compositions comprising cyclosporins |
Non-Patent Citations (1)
Title |
---|
STEVENSON DARA ET AL: "Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease: A dose-ranging, randomized trial", OPHTHALMOLOGY, vol. 107, no. 5, May 2000 (2000-05-01), pages 967 - 974, XP002441123, ISSN: 0161-6420 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20190380958A1 (en) * | 2016-12-28 | 2019-12-19 | Chugai Seiyaku Kabushiki Kaisha | Self-emulsifying drug formulation for improving membrane permeability of compound |
Also Published As
Publication number | Publication date |
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CA2644471A1 (en) | 2007-09-07 |
JP2009529003A (en) | 2009-08-13 |
EP1988879A1 (en) | 2008-11-12 |
US7732404B2 (en) | 2010-06-08 |
US20060205639A1 (en) | 2006-09-14 |
AU2007220104A1 (en) | 2007-09-07 |
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